Now you see it, now you don't: Estrogen exposure and obesity effects on HCA development and regression
Authors: Melinda Wang, Monika Sarkar, Neil Mehta
Journal: Hepatology (2022)

Hepatocellular adenomas (HCAs) are rare benign hepatic tumors commonly associated with exogenous estrogen exposure, particularly in women using combined hormonal contraception (CHC).1 Complications of HCAs include risk of hemorrhage and malignant transformation. The genotype–phenotype classification system of HCAs has defined several subtypes of HCAs with distinct patient, imaging, and pathophysiological characteristics.2 Clinical management of HCAs, including resection/embolization versus watchful waiting, is dependent on size of tumor, sex, β‐catenin activation mutation, and complications. CHC use confers a 30–40‐fold increase in the incidence of HCAs; thus, cessation of these agents is the first step for HCA management.3,4 However, HCA disease course is variable after CHC cessation, suggesting that other factors may contribute to their progression.4,5 In this multicenter study, Demory et al. retrospectively analyzed 183 patients with a total of 267 histologically confirmed HCA lesions. Of these, 96 (52%) underwent treatment, most of which were treated by resection.6 The median age of patients was 38 years old; 88% were women, 22% obese, 45% had a single HCA lesion, and 54% had at least one HCA >5 cm. Among female patients, 89% had CHC use at a median duration of 12 years. The most common HCA subtypes were inflammatory HCA (46%) and B‐catenin HCA (11%). Risk factors for symptomatic bleeding (seen in 11%) were younger age and HCA size >5 cm. Risk factors for malignant transformation (seen in 6%) were male gender and β‐catenin activation mutation. Patients with residual HCA were defined as those with remaining HCA after initial treatment or those patients monitored without intervention. These patients were assessed for HCA evolution using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria at 6 months of follow‐up (n = 122). Overall, 21% had HCA progression, 31% had partial or complete regression, and the remainder had stable disease. Baseline body mass index (BMI) was associated with HCA progression on imaging. Notably, weight loss of >5% among overweight patients was associated with HCA regression in 72% of patients, whereas >5% weight gain among normal‐weight patients was associated with tumor progression. A growing literature now supports the contribution of obesity to incident HCA and HCA growth, including the rising prevalence of HCAs now seen in men.7 The rise in obesity has also contributed to an increased prevalence of inflammatory and β‐catenin‐activated inflammatory HCA subtypes.7 Weight loss is associated with decrease in HCA size, even precluding the need for surgical intervention.5,8 With the prevalence of obesity increasing over time, >5% weight loss among overweight and obese patients with HCA appears to be an important clinical cutoff associated with improved outcome.3 Evaluating the role of obesity treatment on HCA growth, including bariatric surgery or weight loss medications, may be informative.8 Additionally, obesity has been shown to promote HCC development through inflammatory pathways,2,7 although the current study had too few HCC events to evaluate this association.6 No patients in the current study had the sonic hedgehog HCA subtype, which, along with inflammatory HCA subtype, is associated with obesity.1,6 Whether weight loss differentially influences HCA regression by genotype–phenotype classification subtypes remains unclear. The current study therefore provides compelling evidence for the role of weight loss in overweight/obese patients as a cornerstone of HCA management and provides a helpful guide for patients to target >5% of total body weight loss. A second clinically helpful tool for HCA prognosis was a 4‐point estrogen exposure score including duration of CHC use and BMI at diagnosis, which was validated in an external cohort of 72 female patients (Figure 1).6 For example, a patient with ≥12 years of CHC exposure with a BMI ≥ 30 kg/m2 would have an estrogen exposure score of 4, whereas a patient with no CHC exposure with normal BMI < 25 kg/m2 would have a score of 0. Increasing estrogen exposure at baseline was associated with greater probability of tumor regression, with 0% regression in patients with a score of 0, to 70% with regression in patients with a score of 4.FIGURE 1: Overview of hepatocellular adenoma (HCA) regression factors. BMI, body mass index; CHC, combined hormonal contraception.This estrogen exposure score was developed to predict HCA regression among patients who have been treated with intervention or with conservative management using BMI and duration of CHC exposure.6 Overall, the authors found that the same risk factors for HCA development (BMI and CHC exposure) were associated with HCA regression if addressed. The emphasis on HCA regression prediction is interesting. While this endpoint was meant to address the European Association for the Study of the Liver's guideline recommendation to surgically resect tumors >5 cm that do not decrease in size, one could argue that predicting HCA progression may be more clinically relevant than predicting HCA regression (because HCA progression may warrant more aggressive intervention). This scoring system, however, uses modifiable risk factors for HCA formation (obesity and CHC exposure) at baseline to predict HCA regression. Presumably, patients with HCAs who address these risk factors by way of CHC cessation and weight loss would achieve some degree of HCA regression. On the other hand, patients with HCA who lack these risk factors may have more atypical HCA features, making HCA regression less predictable. Therefore, an estrogen exposure score that predicts risk of HCA progression appears helpful for both patient counseling and clinical management to stratify patients into intervention versus close observation. Prior studies have developed HCA regression models using factors such as diameter of HCA at diagnosis, regression over time, and HCA subtype (Figure 1).9 How the estrogen exposure score can be used in conjunction with regression models remains to be seen. Additional studies are needed to assess whether other hormone‐related exposures such polycystic ovary syndrome (PCOS), age of menarche, parity/pregnancy history, and hyperinsulinemia could predict HCA evolution (Figure 1). Clinical endpoints such as HCA progression, bleeding, and malignant transformation were uncommon and thus a limitation of the present study, likely because many patients underwent up‐front surgical resection. Larger multicenter cohorts may be necessary to identify whether these clinical endpoints are associated with the estrogen exposure score. Similar to the present study, a previous estrogen exposure score using duration of CHC, BMI, and alcohol intake has been described.7 Higher estrogen exposure scores were associated with an inflammatory HCA subtype compared with an HNF1A (hepatocyte nuclear factor 1 homeobox A)–mutated HCA subtype.7 In the present study, chronic alcohol use was uncommon (9%), and this variable was not considered. With growing research in the genotype phenotype classification, identifying the contribution of molecular classification to HCA evolution will be useful in clinical management. This study also had limited data regarding switching to progestin‐only contraception. Future studies examining residual HCA evolution should consider the effects of other hormonal therapies and their safety particularly in special populations, including patients with PCOS and transgender patients. Finally, this study used the RECIST 1.1 criteria to characterize HCA evolution.6 HCA literature use varying criteria to describe HCA evolution.4,10 The RECIST criteria were developed to objectively assess changes in tumor burden by anatomical measurements of tumor size with guidelines regarding measurable versus nonmeasurable tumors, number of lesions, lymph nodes, and types of lesions.7 While RECIST criteria were developed for malignancies, HCAs are benign hepatic lesions, and whether RECIST criteria can meaningfully predict clinically important endpoints such as bleeding and malignant transformation in HCA management is unclear. For example, the RECIST criteria highlight the importance of the number of lesions present, but prior HCA studies have demonstrated that number of HCAs does not predict complications.11 Given the importance of studying HCA evolution to provide guidance on frequency of surveillance imaging in conservatively managed patients,10 having a unified definition of HCA evolution would be helpful. This study highlights the need for a unified objective measurement guideline for HCAs, including whether use of RECIST criteria is most appropriate. In summary, in this relatively large multicenter analysis, Demory et al. highlight the role of estrogen exposure and weight changes in HCA evolution,6 which should be considered in algorithms for HCA management. Patients who are obese and have longer duration of CHC exposure ≥ 12 months at baseline are more likely to develop tumor regression, presumably through weight loss and CHC cessation. In other words, CHC exposure and obesity, known factors associated with HCA development, are also associated with regression if addressed. Although these findings and the resulting estrogen exposure score are clinically useful, several questions still remain, including the role of genotype–phenotype classification, how to objectively measure HCA regression, and the generalizability of these data to special populations of patients with endogenous and exogenous hormonal exposure.